Pharmacological strategies to reduce periprocedural bleeding Outpatient PCI Lounge Pharmacological strategies to reduce periprocedural bleeding Jonathan Byrne King’s College Hospital

Delicate balancing act Outpatient PCI Lounge Delicate balancing act Benefit Risk Bleeding Patient factors Procedural factors Pharmacology Ischaemic compications Increasing thrombotic risk usually parallels increased bleeding risk Increasing risk of ischemic complications Increasing risk of bleeding complcations

Pharmacological strategies to reduce bleeding during PCI Outpatient PCI Lounge Pharmacological strategies to reduce bleeding during PCI Reduced dose/no heparin LMW versus unfractionated heparin Newer synthetic anticoaculants Bivalirudin versus heparin/GPI Reduced dose GPI Increasing risk of bleeding complcations Stable ACS High Risk ACS/PPCI

Low dose or ‘no’ dose heparin? Outpatient PCI Lounge Low dose or ‘no’ dose heparin? Current heparin dosages used in PCI are not based on randomised data Current strategies include weight adjusted/ACT adjusted or fixed dose Is it safe to use no heparin in selected ‘low risk’ patients?

Outpatient PCI Lounge CIAO Study 700 stable, elective patients. Type A/B lesions. No adjunctive GPI use 3.7 Event rate (%) Higher procedural CK release in the heparin group (3.1 vs 1.7%) MACE Major Bleeding Stabile JACC 2008

Low fixed dose or weight adjusted? Outpatient PCI Lounge Low fixed dose or weight adjusted? Retrospective analysis of 698 patients Elective PCI Weight adjusted vs fixed dose UFH (3000 units) More complex angiographic lesions than CIAO . Similar levels of TnI release Kidambi Cardiovasc Ther 2010

Outpatient PCI Lounge FUTURA/ OASIS 8 2026 high risk ACS patients within a larger cohort treated with fondaparinux Fixed low dose heparin (50u/kg) compared with ACT guided weight adjusted (85u/kg), regardless of GPI use Major outcome composite of major bleeding at 48 hours FUTURA/OASIS 8 JAMA 2010

No benefit with low dose heparin 5.8 Low use of GPI (20%) ~40% radial access Small reduction in minor bleeds 4.8 4.7 Event rate (%) 3.9 Peri-PCI bleeding/vascular access complications Peri-PCI bleeding/death/MI/TVR FUTURA/OASIS 8 JAMA 2010

STEEPLE- LMWH in elective PCI Outpatient PCI Lounge STEEPLE- LMWH in elective PCI P=0.01 P=0.05 6.5 trend towards higher mortality in the low dose LMWH group 40% GPI use 5.9 5.9 Event rate (%) 5.3 4.8 2.8 1.2 1.2 Major or minor bleeding Major Bleeding Minor bleeding Monatalescot NEJM 2006

Meta-analysis of 13 RCTs Dumaine Arch Intern Med 2007

Avoid crossover from one to the other.. >2000 patients undergoing PCI in the SYNERGY study P=0.047 5.4 P=0.03 Event rate (%) 3.7 2.8 White Am Heart J 2006

Synthetic Xa inhibitors in ACS… Outpatient PCI Lounge Synthetic Xa inhibitors in ACS… Death, MI, refractory ischaemia Major bleeding Primary efficacy endpoint: 5.8% (fondaparinux) vs 5.7% (enoxaparin) Major bleeding: 2.2% (fondaparinux) vs 4.1% (enoxaparin) 1 2 3 4 5 6 7 8 9 0.00 0.01 0.02 0.03 0.04 0.05 0.06 Days Cumulative hazard Enoxaparin Fondaparinux HR 1.01 95% CI 0.90, 1.13 1 2 3 4 5 6 7 8 9 0.00 0.01 0.02 0.03 0.04 Days Cumulative hazard Enoxaparin HR 0.52 95% CI 0.44, 0.61 p<0.001 Fondaparinux OASIS 5 N Engl J Med 2006

Mortality at 6 months Enoxaparin Fondaparinux HR 0.89 Outpatient PCI Lounge Mortality at 6 months Days Cumulative hazard 0.0 0.02 0.04 0.06 20 40 60 80 100 120 140 160 180 Enoxaparin Fondaparinux HR 0.89 95% CI 0.80, 1.00 p=0.05 OASIS 5 N Engl J Med 2006

Bivalirudin in ACS/STEMI Outpatient PCI Lounge Bivalirudin in ACS/STEMI Paucity of data comparing heparin directly with bivalirudin (without GPI) Doses of heparin used in most of the studies are higher than standard UK/European practice

Outpatient PCI Lounge ISAR REACT 3 4570 patients with stable/unstable angina (with no biomarker rise Preloaded with 600mg clopidogrel 140υg/kg UFH compared with bivalirudin Triple end-point; net clinical benefit (MACE + bleeding) Kastrati N Engl J Med 2008

BCIS Autumn Meeting 2008, Stoke on Trent, UK

BCIS Autumn Meeting 2008, Stoke on Trent, UK

ISAR REACT 3a Lower dose (100units/kg) heparin in patients preloaded with clopidogrel ISAR react 3 heparin group used as historical control Same eligibility/exclusion criteria (biomarker negative ACS)

BCIS Autumn Meeting 2008, Stoke on Trent, UK **Almost identical to those seen with bivalirudin in previous study ** ** BCIS Autumn Meeting 2008, Stoke on Trent, UK Kastrati ESC 2010

STEMI- HORIZONS AMI P=0.029 2.9% Death (%) 1.8% Time in Days 2.9% 1.8% Heparin + GPIIb/IIIa inhibitor (n=1802) Bivalirudin monotherapy (n=1800) 0.3% 0.2% Cardiac Non cardiac HR [95%CI] = 0.62 [0.40, 0.96] P=0.029 Stone NEJM 2008

HORIZONS-AMI 30 day outcomes Stone NEJM 2008

Reduced dose GPI? Early data (EPIC) suggested reduced bleeding but higher ischaemic complications with bolus abciximab EASY PCI (transradial) - clopidogrel loading. no difference between bolus/infusion of abciximab. Bleeding rates 0.5% (TRI) BRIEF PCI – ~700 patients (stable/ACS). Transfemoral. Clopidogrel preloaded. 2 hour versus 18 hour eptifibatide infusion

Lower major bleeding rates 21.2 17.6 ~40% ACS 97% femoral access Event Rate (%) P=0.02 4.2 1 Major Bleeding Minor Bleeding Fung JACC 2009

Conclusions Tailored treatment for individual patients to balance thrombotic/bleeding risk. Stepwise approach to antithrombotics with increasing bleeding risk Avoid switching between antithrombins (except UFH from fondaparinux) Pharmacology should be coupled with other bleeding avoidance strategies (TRI in particular)